Necroptosis and RIPK1-mediated neuroinflammation in CNS diseases

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Abstract

Apoptosis is crucial for the normal development of the nervous system, whereas neurons in the adult CNS are relatively resistant to this form of cell death. However, under pathological conditions, upregulation of death receptor family ligands, such as tumour necrosis factor (TNF), can sensitize cells in the CNS to apoptosis and a form of regulated necrotic cell death known as necroptosis that is mediated by receptor-interacting protein kinase 1 (RIPK1), RIPK3 and mixed lineage kinase domain-like protein (MLKL). Necroptosis promotes further cell death and neuroinflammation in the pathogenesis of several neurodegenerative diseases, including multiple sclerosis, amyotrophic lateral sclerosis, Parkinson disease and Alzheimer disease. In this Review, we outline the evidence implicating necroptosis in these neurological diseases and suggest that targeting RIPK1 might help to inhibit multiple cell death pathways and ameliorate neuroinflammation.

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Induction of TNF receptor I-mediated apoptosis via two sequential signaling complexes.

Olivier Micheau, Jurg Tschopp (2003)

Apoptosis induced by TNF-receptor I (TNFR1) is thought to proceed via recruitment of the adaptor FADD and caspase-8 to the receptor complex. TNFR1 signaling is also known to activate the transcription factor NF-kappa B and promote survival. The mechanism by which this decision between cell death and survival is arbitrated is not clear. We report that TNFR1-induced apoptosis involves two sequential signaling complexes. The initial plasma membrane bound complex (complex I) consists of TNFR1, the adaptor TRADD, the kinase RIP1, and TRAF2 and rapidly signals activation of NF-kappa B. In a second step, TRADD and RIP1 associate with FADD and caspase-8, forming a cytoplasmic complex (complex II). When NF-kappa B is activated by complex I, complex II harbors the caspase-8 inhibitor FLIP(L) and the cell survives. Thus, TNFR1-mediated-signal transduction includes a checkpoint, resulting in cell death (via complex II) in instances where the initial signal (via complex I, NF-kappa B) fails to be activated.

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Identification of a molecular signaling network that regulates a cellular necrotic cell death pathway.

Junichi Hitomi, Dana E Christofferson, Aylwin Ng … (2008)

Stimulation of death receptors by agonists such as FasL and TNFalpha activates apoptotic cell death in apoptotic-competent conditions or a type of necrotic cell death dependent on RIP1 kinase, termed necroptosis, in apoptotic-deficient conditions. In a genome-wide siRNA screen for regulators of necroptosis, we identify a set of 432 genes that regulate necroptosis, a subset of 32 genes that act downstream and/or as regulators of RIP1 kinase, 32 genes required for death-receptor-mediated apoptosis, and 7 genes involved in both necroptosis and apoptosis. We show that the expression of subsets of the 432 genes is enriched in the immune and nervous systems, and cellular sensitivity to necroptosis is regulated by an extensive signaling network mediating innate immunity. Interestingly, Bmf, a BH3-only Bcl-2 family member, is required for death-receptor-induced necroptosis. Our study defines a cellular signaling network that regulates necroptosis and the molecular bifurcation that controls apoptosis and necroptosis.

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Cleavage of the death domain kinase RIP by caspase-8 prompts TNF-induced apoptosis.

Y. Lin, A. Devin, Y. Rodríguez … (1999)

Although the molecular mechanisms of TNF signaling have been largely elucidated, the principle that regulates the balance of life and death is still unknown. We report here that the death domain kinase RIP, a key component of the TNF signaling complex, was cleaved by Caspase-8 in TNF-induced apoptosis. The cleavage site was mapped to the aspartic acid at position 324 of RIP. We demonstrated that the cleavage of RIP resulted in the blockage of TNF-induced NF-kappaB activation. RIPc, one of the cleavage products, enhanced interaction between TRADD and FADD/MORT1 and increased cells' sensitivity to TNF. Most importantly, the Caspase-8 resistant RIP mutants protected cells against TNF-induced apopotosis. These results suggest that cleavage of RIP is an important process in TNF-induced apoptosis. Further more, RIP cleavage was also detected in other death receptor-mediated apoptosis. Therefore, our study provides a potential mechanism to convert cells from life to death in death receptor-mediated apoptosis.